delta-7-keto-11-bromo-steroids and the processes of preparing them



United States Patent A -7-KET0-1l-BROMO-STEROIDS AND THE PROCESSES OF PREPARING THEM John M. Chemerda, Metuchen, N. J., assignor to Merck & Co., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Application October 5, 1953 3 Serial No. 384,319

13 Claims. (Cl. 260239.55)

This invention is concerned generally with steroid compounds having an oxygen atom attached to the carbon atom in the ll-position of the molecule. More particularly, it relates to 7-keto-ll-(keto, hydroxy or acyloxy)- cyclopentanopolyhydrophenanthrene compounds, and with processes for preparing these compounds starting with the corresponding A -7-keto-1l-(hydroxy, bromo or acyloxy)-cyclopentanopolyhydrophenanthrene compound. The 7-keto-1l-(keto, hydroXy or acyloxy)-cyclopentanopolyhydrophenanthrene compounds thus obtained are valuable as intermediates in the synthesis of steroid hormones having an oxygen atom attached to the ll-carbon atom, such as the adrenal hormones corticosterone, cortisone and Compound F.

This application is a division of my co-pending application, Serial No. 240,281, filed August 3, 1951, now Patent No. 2,749,337, issued June 5, 1956.

The 7-keto-11-(keto, hydroxy or acyloXy)-cyclopentanopolyhydrophenanthrene compounds subject of the present invention have at rings B and C the following chemical structure:

wherein R represents a keto, hydroxy or acyloxy substituent.

These 7 keto 11 (keto, hydroxy or acyloXy)-cyclopentanopolyhydrophenanthrene compounds can be prepared as follows: A A -7-keto-ll-acyloxy-cyclopentanopolyhydrophenanthrene compound (Compound 1 hereinbelow) or a 11 7-keto-11-hydroxy-cyclopentanopolyhydrophenanthrene compound (Compound 2) is reacted with a reducing agent thereby forming, respectively, the corresponding 7 keto-1 1-acyloxy-cyclopentanopolyhydrophenanthrene compound (Compound 3) or the corresponding 7 keto 11 hydroxy-cyclopentanopolyhydrophenanthrene compound (Compound 4); alternatively, if desired, the 7 keto ll-hydroxy-cyclopentanopolyhydrophenanthrene compound can be prepared by reacting the 7 keto 11-acyloXy-cyclopentanopolyhydrophenanthrene compound with a hydrolyzing agent; this 7-keto-1l-hydroxy cyclopentanopolyhydrophenanthrene compound (Compound 4-) is then reacted with an oxidizing agent to produce the corresponding 7,11-diketo-cyclopentanopolyhydrophenanthrene compound (Compound 5); alterna-' tively, said 7,11 diketo cyclopentanopolyhydrophenanthrene compound can be prepared by reacting the corresponding A 7 keto 11 hydroxy-cyclopentanopolyhydrophenanthrene compound (Compound 2) with an alcoholic alkali metal hydroxide at an elevated temperature of approximately 150 C.; or if desired by reacting the corresponding A -7-keto-1'1-bromo-cyclopentanopolyhydrophenanthrene compound (Compound 6) Reducing agent Compound 1 Hydroz s agent no? no Reducing i agent O 0 Compound 2 Compound 4 woholic alkali Oxidizin metal agent 0. hydroxide zpk Alcoholic mineral r acid r. :0 0

Compound 6 Compound 5 cholestene, A 3,11 dihydroxy 7 keto cholestene,

A 3,11 diacyloxy 7 keto cholestene, A 3,11-- dialkanoxy 7 keto cholestene, A 3,11 diacetoxy- 7 keto cholestene, A 3,11 dihydroxy 7 ketostigmastadiene, A -3,11 -diacyloxy 7-keto-stigrnasta:

diene, A 3,1'1 dialkanoxy- 7-keto-stigmastadiene,

A -3 ,1'1 diacetoxy 7 keto stigmastadiene, a bileacid side chain attached to the l7-carbon atom such as A -3,11-dihydroXy 7 keto cholenic acid, A -3,11- diacyloxy 7 keto ,cholenic acid, A 3,11 dihydroxy 7 keto-allocholenic acid, A -3,11-diacyloxy-7-' keto-a'llocholenic acid, a degraded bile acid side chain attached to the 17-carbon atom such as A -3,11-dihydroX 7 keto bisnorlcholenic acid, A -3,11-diacyloxy- 7-keto-bisnorcholenic acid, A 3,11 -dihydrox-y-7-ketobisnorallocholenic acid, A -'3,11 diacyloxy 7;- ketobisnoral'locholenic acid, a l7-carboxyl substituent such as 13 7 keto -,1 1 hydroxy etiocholenic ac-id, A -I3.,,- 11 dihydroxy 7 keto etiocholenic acid, A '3,-1;1- diacyloxy 7 keto etiocholenic acid, A wi ll-dihydroxy-7-keto-etioallodholenic acid, ,A -3,1l-diacy1oxy-'7 keto-etioallocholenic acid, a 17-,acetyl substituent such .as, A 3,11 dihydroxy 7 keto pregnene, A 3,11

diacyloxy 7 keto pregnene, A 3,11 dihydroxy-7- i, 3 keto-allopregnene,A 3,11 diacyloxy 7 keto-allopregnene, a sapogenin side chain such as A -7-keto-11- hydroxy-dehydrotigogenin, A 7 keto 11 acyloxydehydrotigogenin acylate, 13 7 keto 11 alkanoxyd ehydrotigogenin alkanoate, A 7 keto -11-acetoxy-dehydrotigogenin acetate and the like. These starting materials can be prepared according to the procedures set forth'in detail in my co-pending application Serial No. 240,052, filed August 2, 1951, now Patent No. 2,734,897, issued February 14, 1956. The A -7-keto-11-(acyloxy or hydroxy)-cyclopentanopolyhydrophenanthrene starting material is reacted with a reducing agent to produce the corresponding 7 keto 11 (acyloxy or hydroxy)-cyclopentanopolyhydrophenanthrene compound. This reduction reaction is ordinarily carried out by bringing the A 7-keto-11-(acyloxy or hydroxy)-cyclopentanopolyhydrophenanthrene compound in intimate contact with zinc dust and acetic acid or, if desired, hydrogen in the presence of a platinum catalyst. The 7-keto-1l-(acyloxy or hydroxy) cyclopentanopolyhydrophenanthrene compounds obtained according to this reduction procedure include A -7-keto-1l-acyloxy-ergostene, A -3,11-dihydroxy- 7-keto-ergostene, A 311-diacyloxy-7-keto-ergostene, A 3,11 dialkanoxy 7 keto-ergostene, A -3,11-diacetoxy- 7-keto-ergostene, 7-keto-1l-acyloxy-cholestane, 7-keto-11- hydroxy-cholestane, 3,11 dihydroxy 7 keto-cholestane, 3,11 diacyloxy 7 keto cholestane, 3,11 dialkanoxy- 7-keto-cholestane, 3,11-diacetoxy-7-keto-cholestane, A -3,- 11 dihydroxy 7 keto stigmastene, A -3,11-diacyloxy- 7 keto stigmastene, A 3,11 diacetoxy-stigmastene, 3,11 dihydroxy 7 keto-cholanic acid, 3,11-diacyloxy-7- keto-cholanic acid, 3,11-dialkanoxy-7-keto-cholanic acid, 3,11 diacetoxy 7 keto-cholanic acid, 3,11-dihydroxy-7- keto-allocholanic acid, 3,11-diacyloxy-7-keto-allocholanic 4 acid, 3,11 dihydroxy 7 keto bisnorcholanic acid,

3,11 diacyloxy 7 keto bisnorcholanic acid, 3,11- dialkanoxy 7 keto bisnorcholanic acid, 3,11 diacetoxy 7 keto bisnorcholanic acid, 3,11 dihydroxy- 7 keto bisnorallocholanic acid, 3,11 diacyloxy-7-ketobisnorallocholanic acid, 3,11 dihydroxy 7 keto etiocholanic acid, 3,11 diacyloxy 7 keto-etiocholanic acid, 3,11 diacetoxy 7 keto-ethiocholanic acid, 3,11-dihydroxy 7 keto etioallocholanic acid, 3,11-diacy1oxy-7- keto etioallocholanic acid, 3,11 dihydroxy-7-keto-pregnane, 3,11 diacyloxy 7 keto-pregnane, 3,11-diacetxy- 7-- keto-pregnane, 3,11 dihydroxy-7-keto-allopregnane, 3,11 diacyloxy 7 7 keto-allopregnane, 3,11 diacylovy- 7 keto-allopregnane, 7 keto 11 hydroxy tigogenin, 7- keto 11 acyloxy-tigogenin acylate, 7 keto 11-alkanoxytigogenin alkanoate, 7 keto-1l-acetoxy-tigogenin acetate, and the like.

Where the Aw -7-keto-cyclopentanopolyhydrophenanthrene compound'utilized as starting material in the reduction procedure described hereinabove contains an acyloxy substituent in the ll-position thereby producing the corresponding A -7-keto-11-acyloxy-cyclopentanopolyhydrophenanthrene, this latter compound can be converted to the corresponding 7 keto 11 hydroxy-cyclo pentanopolyhydrophenanthrene compound, if desired, by reaction with a hydrolyzing agent. We ordinarily utilize as the hydrolyzing agent in carrying out this reaction, an alcoholic solution of an alkali metal hydroxide such as ethanolic potassium hydroxide, methanolic potassium hydroxide, methanolic sodium hydroxide, and the like.

The 7-keto-11-hydroxy-cyclopentanopolyhydrophenanthrene compound is then reacted with an oxidizing agent, such as chromic acid, thereby forming the corresponding 7,11 -diketo-cyclopentanopolyhydrophenanthrene compound. This oxidation reaction, where chromic acid is used as the oxidation agent is conveniently conducted by dissolving 7 keto 11 hydroxy-cyclopentanopolyhydrophenanthrene compound in an organic solvent substantiallyinert to chromic acid such as acetone, adding to the resulting solution a solution'containing chromic acid dissolved in aqueous sulfuric acid, and allowing the mixture 4 to react substantially at room temperature for a period of approximately one hour. In accordance with this procedure, there is obtained the desired 7,11-diketo-cyclopentanopolyhydrophenanthrene compound such as A- 7,11-diketo-ergostene, A -3-acyloxy-7,1l-diketo-ergostene, A 3 acetoxy 7,11-diketo-erogstene, A -7,11-hydroxy- 7,11 diketo-ergostene, 7,11-diketo-cholestane, 3-acyloxy- 7,11 diketo-cholestane, 3-acetoxy-7,1l-diketo-cholestane,

3 hydroxy 7,11 diketo cholestane, A 3 hydroxy 7,11 diketo stigmastene, A 3 acyloxy 7,11-diketostigmastene, A 3 acetoxy 7,11 diketo-stigmastene, 3 hydroxy 7,11 diketo-cholanic acid, 3-acyloxy-7,11- diketo-cholanic acid, 3-acetoxy-7,1l-diketo-cholanic acid, 3 hydroxy-7,1l-diketo-allocholanic acid, 3-acyloxy-7,11- diketo allocholanic acid, 3 acetoxy 7,11 diketo-allocholanic acid,. 3-hydroxy-7,1l-diketo-bisnorcholanic acid, 3-acyloxy-7,1l-diketo-bisnorcholanic acid, 3-hydroxy-7,11- diketo-bisnorallocholanic acid, 3 acyloxy 7,11 diketobisnorallocholanic acid, 3 hydroxy 7,11-diketo-etiocho-,

rearrangement of the hydrogen atoms attached respectively to the C-11-carbon atom and to the oxygen of the ll-hydroxy substituent to the carbon atoms in the 8 and 9-,positions thereby saturating the A -double bond. It is ordinarily preferred to conduct this reaction by heating the A 7 keto-11-hydroxy-cyclopentanopolyhydrophenanthrene compound with the alcoholic solution of an alkali metal hydroxide such as ethanolic potassium hydroxide, methanolic potassium hydroxide, methanolic sodium hydroxide, and the like,'at a temperature of approximately -150 C. At this temperature the reaction is ordinarily substantially complete after a heating period of approximately eight hours.

Instead of utilizing A -7-keto-11-(acyloxy or hydroxy)-cycl0pentanopolyhydrophenanthrene compounds as starting materials for the preparation of the desired 7,11 diketo cyclopentanopolyhydrophenanthrene compounds, We can employ, instead, the corresponding A 7- keto 11 bromo cylopentanopolyhydrophenanthrene compound, such as A -7-keto-ll-bromo-ergostadiene, 13 -3-hydroxy-7-keto-1 l-bromo-ergostadiene, A 3 acyloxy 7 keto 11 bromo-ergostadiene, A -3- alkanoxy 7 keto 11 bromo ergostadiene, M -3- acetoxy 7 keto 11 bromo-ergostadiene, A -7-keto- 1 l-bromo-cholestene, A -3-hydroxy-7-keto-1l-brorno cholestene, A -3-acyloxy-7-keto-1l-bromo-cholestene, A -3-alkanoxy-7-keto-11-bromo-cholestene, A -3-acetoxy-7-keto 11 bromo-cholestene, A -3-hydroxy-7- keto-1l-bromo-stigmastadiene, A -3-acyloxy-7-keto- 11 bromo stigmastadiene, A 3 alkanoxy 7- keto 11 bromo stigmastadiene, A 3 alkanoxy 7 keto 11- bromo stigmastadiene, A 3 acetoxy 7 keto 11 bromo stigmastadiene, A 3 hydroxy 7 keto 11 bromo cholenic acid, A 3 acyloxy 7 keto 11 bromo cholenic acid, A 3 hydroxy 7 keto 11 bromo allocholenic acid, 38(9) 3 acyloxy 7 keto 11 bromoallocholenic acid, m) 3 hydroxy 7 keto llbromo bisnorcholenic acid, A 3 acyloxy 7- keto 11 bromo bisnorcholenic acid, A 3 hydroxy 7 keto 11 bromo bisnorallocholenic acid, A a 3 acyloxy 7 keto 11*- bromo bisnorallocholenic acid, A 3 --hydroxy 7 keto l1 bromoetiocholenic acid, A803) 3 acyloxy 7 keto 11- bromo etiocholenic acid, A 3 hydroxy 7 keto- 11 bromo etioallocholenic acid, A 3 acyloxy- 7 keto 11 bromo etioallocholenic acid, A 3- hydroxy 7 keto 11 bromo pregnene, A 3- acyloxy 7 keto l1 bromo pregnene, A 3 hydroxy 7 keto 11 bromo allopregnene, A 3- acyloxy 7 keto l1 bromo allopregnene, A 7 keto 11 bromo dehydrotigogenin, A 7 keto- 11 bromo dehydrotigogenin acylate, A 7 kctol1 bromo dehydrotigogenin alkanoate, A 7- keto 11 bromo dehydrotigogenin acetate, and the like. These compounds can be obtained by reacting N- bromosuccinimide with the corresponding A -7- acyloxy-cyclopentanopolyhydrophenanthrene compound, which in turn, can be prepared in accordance with the procedures set forth in my co-pending application Serial No. 240,052, filed August 2, 1951. The A -7-keto1l bromo-cyclopentanopolyhydrophenanthrcne compound is reacted with an alcoholic solution of a mineral acid, preferably a solution of hydrochloric acid in methanol. The reaction is conveniently carried out by heating the reactants together under reflux thereby producing the corresponding 7,1 1-diketo-cyclopentanopolyhydrophenanthrene compound.

The following examples illustrate methods of carryout the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 One hundred milligrams of A -3,11-diacetoxy-7- keto-ergostadiene (which can be prepared according to the procedure described in my co-pending application Serial No. 240,052, filed August 2, 1951), was dissolved in cc. of acetic acid, 100 mg. of zinc dust was added to the solution, and the resulting mixture was heated at a temperature of 100 C. for about three hours. The reaction mixture was filtered, the filtered solution was diluted with water, and the gummy material which precipitated was extracted with benzene. The benzene was evaporated from the benzene extract to give A -3,11-diacetoxy-7-keto-ergostene which was obtained in the form of an amorphous solid.

The A -3,11-diacetoxy-7-keto-ergostene, prepared as described hereinabove, was dissolved in 5 cc. of a 5% solution of sodium hydroxide in methanol and the resulting solution was heated under reflux for a period of approximately one hour. luted with water and the gummy material which precipitated was recovered by decantation, washed and dried to give A -3,ll-dihydroxy-7-keto-ergostene in the form of an amorphous solid.

The A -3,11-dihydroxy-7-keto-ergostene, prepared as described hereinabove, was dissolved in 5 cc. of acetone, and a solution containing 7 mg. of chromic acid dissolved in 1 cc. of 2 N aqueous sulfuric acid solution was added to the acetone solution. The resulting mixture was allowed to stand at room temperature for a period of about twenty minutes, the solvents were evaporated from the reaction solution in vacuo, and the residual material was extracted with ether. The ethereal extract was chromatographed over acid-washed alumina to give substantially pure A -3-hydroxy-7,l1-diketo-ergostene; M. P. 199-200" C.

Example 2 One hundred milligrams of M -3,1l-dihydroxy-7- keto-ergostadiene were dissolved in 15 cc. of alcohol, 20 mg. of platinum oxide catalyst were added to the solution, and the resulting mixture was subjected to the action of hydrogen at a pressure of one atmosphere until one molecular equivalent of hydrogen had been absorbed. The reaction mixture was filtered, thereby removing the catalyst, and the filtered solution was evapo- The reaction solution was dirated in vacuo to give A -3,11-,dihydroxy-7-,keto ergostene which was obtained as an amorphous solid.

The A -3,11-dihydroxy-7-keto-ergostene, prepared as described in the preceding paragraph, was dissolved in 10 cc. of acetone, and a solution containing 7 mg. of chromic acid dissolved in 1 cc. of a 2 N aqueous solution of sulfuric acid was added to the acetone solution. The resulting mixture was allowed to stand at room temperature for a period of about twenty minutes, the solvents were evaporated from the reaction solution in vacuo, and the residual material was extracted with ether. The ethereal extract was chromatographed over acid-washed alumina to give substantially pure A -3-hydroxy-7,11-diketo-ergostene; M. P. 199-200 C.

Example 3 One hundred milligrams of A' -3,7-diacetoxy-9,11- epoxy-ergostadiene (which can be prepared according to the procedure described in my co-pending application Serial No. 240,052, filed August 2, 1951), were heated under reflux with 5 cc. of a 5% solution of potassium hydroxide in methanol. (The alkaline methanolic reaction solution, thus prepared, contains A -3,l1-dihydroxy-7-keto-ergostadiene which can be recovered therefrom, if desired, by evaporating the methanol from the solution in vacuo, triturating the residual solution with water, and filtering and drying the precipitated material.)

Instead of isolating the A -3,l1-dihydroxy-7-ketoergostadiene, the alkaline methanolic reaction solution containing this compound was heated under pressure at a temperature of about C. for a period of approximately eight hours. The reaction mixture was cooled to room temperature, water was added thereto, and the material which precipitated was recovered by filtration and purified by chromatography over acid-washed alumina to give substantially pure A -3-hydroxy-7,11-diketo-ergostene; M. P. 198-200 C.

Example 4 Two hundred milligrams of A' -3,7-diacetoXy- Ef g 136 Analysis.-Calcd for C H O Br: Br, 14.9. Found: Br, 14.1.

Two hundred milligrams of A -3-acetoxy-7-ketoll-bromo-ergostadiene were dissolved in 30 cc. of methanol, 0.1 ml. of a 2.5 N aqueous solution of hydrochloric acid was added to the methanol solution, and the resulting solution was heated under reflux for a period of about three hours. The solvents were evaporated from the reaction solution in vacuo, and the residual material was chromatographed over acid-washed alumina to give substantially pure A -3-hydroxy-7,1l-diketoergostene; M. P. 196198 C.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of my invention.

I claim:

1. The process which comprises reacting a A' -7- acyloxy-cyclopentanopolyhydrophenanthrene compound selected from the group which consists of A -3J- bis(lower alkanoyloxy) -ergostatriene and A' -7-(lower alkanoyloxy)-bisdehydrotigogenin 3-(lower alkanoate) with an N-bromoamide thereby forming the correspond ing A 7 keto 11 bromo cyclopentanopolyhydrophenanthrene compound, and reacting the latter compound with an aqueous mineral acid to produce the corresponding 7,11 diketo cyclopentanopolyhydrophenanthrene compound.

2. The process which comprises reacting A -3,7- diacetoXy-ergostatriene with N-bromosuccinimide to produce A -3-acetoxy-7-keto-1l-bromoergostadiene, and reacting the latter compound with an aqueous solution of hydrochloric'acid to form A -3-hydroXy-7,1l-diketo-ergostene.

3. The process which comprises reacting A -7- acetoxy-bisdehydrotigogenin acetate with N-bromosuccinimide to produce A -7 keto 11 brornodehydrotigogenin acetate, and reacting the latter compound with an aqueous solution of hydrochloric acid to produce 7,11- diketotigogenin.

4. The process which comprises reacting a A -7-ketol1 bromo cyclopentanopolyhydrophenanthrene compound selected from the group which consists of N 3 (lower alkanoyloxy) 7 keto 11 bromo ergostadiene and A -7-keto-l l-bromodehydrotigogenin 3-(1ower alkanoate) with an aqueous mineral acid to produce the corresponding 7,11 diketo cyclopentanopolyhydrophenanthrene compound.

5. The process Which comprises reacting A -3- acetoxy-7-keto-1l-bromo-ergostadiene with an aqueous solution of hydrochloric acid to produce A -3-hydrox 7,1 l-diketo-ergostene.

6. The process which comprises reacting A -7-keto- 1l-bromo-dehydrotigogenin acetate with an aqueous solution of hydrochloric acid to produce 7,11-diketo-tigogenin.

.7. A A -7-keto-11-bromocyclopentanopolyhydrophenanthrene compound selected from the group which consists of .A -3-(lower alkanoy1oxy)-7-keto-ll-bromoergostadiene and A -7-keto-1l-bromo-dehydrotigogenin 3- (lower alkanoate) having, respectively, the following formulae:

g RO C -0 and wherein R is a lower alkanoyl radical.

8 t 8. A 3 acetoxy 7 keto 11 bromo ergostadiene having the following formula:

CHaC OO I 9. [1 7 keto 11 bromo dehydrotigogenin acetate having the following formula:

on. CH.. Br I? 10. A 7 kcto 11 bromo dehydrotigogenin having the following formula:

No references cited. 

8. $8(9),22 - 3 - ACETOXY - 7 KETO - 11 - BROMO - ERGOSTADIENE HAVING THE FOLLOWING FORMULA:
 10. $8(9) - 7 - KETO - 11 - BROMO - DEHYDROTIGOGENIN HAVING THE FOLLOWING FORMULA: 